oa Anti-allergic effects by arginase inhibitors: Role of nitric oxide

Anti-allergic effects by arginase inhibitors: role of nitric oxide Herman Meurs¹, Ramadan Sopi¹´², Mirjam Simoons¹, Paul Jackson³, Harm Maarsingh¹´³ ¹Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy and Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, The Netherlands, ²Faculty of Medicine, University of Prishtina, Prishtina, Kosovo, ³Department of Pharmaceutical Sciences, Gregory School of Pharmacy, Palm Beach Atlantic University, West Palm Beach, FL, USA Using animal models for acute and chronic asthma, we demonstrated that inhaled arginase inhibitors attenuate allergen-induced early and late asthmatic reactions, airway hyperresponsiveness, airway inflammation and airway remodeling. Moreover, it was found that arginase inhibition greatly reduces the sensitivity of the airways to the inhaled allergen, suggesting that arginase inhibitors may have an anti-allergic effect by inhibition of mediator release from mast cells. Since arginase activity regulates nitric oxide (NO) synthesis via competition with NO synthase (NOS) for the common substrate L-arginine, and activation of mast cells is inhibited by NO, we hypothesized that the anti-allergic effect of arginase inhibition involves increased NO synthesis. This hypothesis was investigated in precision-cut lung slices from actively ovalbumin (OVA)-sensitized guinea pigs, by using video-assisted microscopy to measure allergen (OVA)-induced airway constriction. OVA induced a dose-dependent airway constriction with a mean maximal effect (Emax) of 98% and a mean EC50 of 0.039 µg/ml. The arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH, 1 µM) significantly reduced the sensitivity towards OVA by >100-fold to 5 µg/ml, whereas the Emax of OVA was reduced to 50%. The effects of ABH were mimicked by the arginase inhibitor N?-hydroxy-nor-L-arginine (nor-NOHA, 5 µM). The NOS inhibitor N?-nitro-L-arginine methyl ester (L-NAME, 100 µM) largely reversed the inhibitory effect of ABH, indicating the involvement of NO. Remarkably, inhibition of arginase and/or NOS did not affect airway constriction towards exogenous histamine, the primary contractile mediator released by mast cells upon allergen challenge. This indicates that ABH reduces the histamine release from mast cells rather than the responsiveness to this mediator. In conclusion, inhibition of arginase greatly reduces airway responsiveness towards allergen by increased NO synthesis, most likely preventing mediator release from mast cells and subsequent airway constriction. Supported by the European Erasmus Mundus partnership JoinEU-SEE